Taming Keteniminium Reactivity by Steering Reaction Pathways: Computational Predictions and Experimental Validations

Keteniminium ions, the nitrogen analogues of ketenes, exhibit high reactivity toward olefins and π-systems. Previous results from the Maulide group demonstrated an unexpected propensity for an alternative intramolecular Belluš–Claisen-type rearrangement rather than an expected intramolecular (2 + 2) cycloaddition. We have conducted a cooperative density functional theory/experimental investigation of this process, seeking insights into the competition between the observed Claisen-type reaction and the historically expected (2 + 2) cyclization. Our calculations revealed a surprisingly small difference in the free energy barrier between these two intramolecular reactions. Further theoretical and experimental investigations probe the electronics of the substrate, rationalize a competing deallylation side reaction, and demonstrate the proof-of-concept for an enantioselective (2 + 2) variant.


■ INTRODUCTION
Ketenes hold a storied place in the organic chemist's toolbox. 1−3 Since Staudinger's disclosure of the species in 1905 (Scheme 1, top left), 4 ketenes have enabled the synthesis of cyclobutanone scaffolds through a prototypical thermal ( π 2 s + π 2 a ) reaction with olefins 5−7 and have also served as critical rearrangement intermediates (e.g., Wolff rearrangement, 8,9 among numerous others 1,2,10 ). This prodigious reactivity is, however, often detrimental, as the desired ketene transformation may be plagued by side reactivity or dimerization. 11−13 The generation of ketenes also often requires the use of sensitive intermediates (e.g., acyl chlorides) or high temperatures, which may pose challenges in complextarget synthesis or when delicate substrates are employed.
A variety of ketene equivalents and analogues have been formulated to temper errant reactivity and enable access to ketene-like behavior from convenient functional groups. 14−17 The keteniminium ion, introduced by Ghosez and co-workers, represents a particularly convenient equivalent (Scheme 1, top right). 18−23 Through the action of an electrophile (such as phosgene or, more typically, triflic anhydride) and a base, otherwise stalwart carboxamides can be transiently converted to keteniminium ions and subsequently engaged in polar chemistry. In addition to the ease of generation, keteniminium ions are less prone to dimerization and offer a particularly useful handle to manipulate selectivity through additional bonds to nitrogen. 24 Seeking to leverage the reactivity and selectivity of keteniminium ions in a total synthesis campaign, the Maulide group in 2010 attempted the synthesis of cyclobutanonetetrahydropyran bicycle 6 (Scheme 1, bottom). 25−27 However, unlike related literature precedents for this reaction, the presence of an ethereal oxygen instead triggered a Bellus− Claisen-type rearrangement, furnishing allyl γ-lactones (4). 19,28,29 None of the classic (2 + 2) product 6 was reported, and we sought to understand the factors controlling these two competing intramolecular reactions. In the process of our investigation, we engaged in a computational/experimental collaboration. The synergy between experiment and theory enabled a thorough investigation of the cycloaddition capacity of this reaction and uncovered methods by which the chemoselectivity of the reaction can be dramatically altered.

■ METHODS
Quantum mechanical investigations of the reactions of keteniminium ion 2 and congeners were conducted with density functional theory (DFT) calculations using Gaussian 16. 30 Initial geometries were prepared with Grimme's xTB 31 /CREST 32 and Zimmerman's GSM 33 codes. Geometry optimization was completed at the ωB97X-D/def2-SVP level with the solvation model based on density (SMD) for dichloromethane. 34−36 Single-point corrections to energy were made at the ωB97X-D/def2-TZVPP level with the SMD for dichloromethane. Quasiharmonic corrections to enthalpy and entropy were made using Paton's GoodVibes software. 37 ■ RESULTS AND DISCUSSION Initial Studies. Our computational investigations began with the mechanism proposed by Maulide et al. for the conversion of amide 1 to allyl lactone 4 ( Figure 1). 25 We located intermediates and transition structures (TSs) with favorable energetics proceeding from the parent amide to the  keteniminium ion 2. The reversible addition of the collidine base to 2 was also established, with the resulting adduct demonstrating substantial stabilization of the keteniminium ion (see Supporting Information, section 5.3). 41,42 Unlike the generation of keteniminium ions from ynamides�which is known to be endergonic 43 �this process is considerably exergonic (ΔG = −32.7 kcal/mol; see Supporting Information section 5.4 for ynamide model study). Keteniminium ion 2 adopts a low-energy conformation where the ethereal oxygen interacts with the π* orbital (n → π*, Figure 1 inset); 44 this conformation essentially preorganizes the scaffold to proceed to the key allyloxonium ion species 9 (ΔΔG ⧧ = 10.7 kcal/mol; see Supporting Information, section 5.5). 43,45,46 From 9, we located Claisen-type TSs for the allyl rearrangement, the lower-energy chair conformer of which exhibits a reasonable energy barrier of 18.9 kcal/mol (TS-3). 47 This keteniminium ion 2 also permitted us to identify a (2 + 2) TS (TS-4), proceeding to the cis-cyclobutane iminium ion 5 (cis-(2 + 2) adduct), that is only 2.4 kcal/mol higher in energy than the Claisen chair (see inset in Figure 1). This free energy difference is consistent with the previous report that only lactone product 4 was observed. 48 However, 2.4 kcal/mol is not a particularly large free energy gap, and we hypothesized that small perturbations to the olefin electron density may promote (2 + 2) reactivity over the Claisen-type rearrangement.
Obtaining (2 + 2) Products. We next studied the methallyl congener 10, which exhibited an energetic profile similar to that of the unsubstituted parent substrate 1, until the formation of the keteniminium ion 11 (see Supporting Information, section 5.6). Following on from 11, we were gratified that the minor inductive electron donation of the methyl group was sufficient to remove the relative energy barrier between the chair sigmatropic rearrangement and the cis-(2 + 2) TSs (ΔΔG ⧧ = −0.3 kcal/mol, Scheme 2).  While the initial report of this reaction for methyl olefin substrate 10 did not identify any of the (2 + 2) bicyclic product 13�instead reporting a 61% yield of allyl lactone 12 25 �the corresponding essentially isoenergetic transition structures (TS-5 and TS-6, Scheme 2) suggest that the (2 + 2) reaction should be a competitive pathway. This computational prediction was readily tested experimentally. Gratifyingly, conducting the experiment utilizing modern, mild amide activation procedures 49 (Scheme 3A, 2-fluoropyridine at 20°C ; see Supporting Information, section 2.3) allowed us to obtain a 15% yield of the cis-(2 + 2) cycloaddition product 13. This result confirms that it is possible to steer the reaction pathway by modulating the olefin electronic traits. Notably, subjecting the unsubstituted olefin substrate 1 to these conditions provided an 85% NMR yield of the corresponding allyl lactone 4 with no evidence of the corresponding (2 + 2) cycloadduct 6. A significant byproduct exhibiting NMR spectroscopic signals indicative of a trans-(2 + 2) cycloaddition product was also identified. Both 13 and this unexpected byproduct resisted crystallization but were successfully identified by X-ray diffraction spectroscopy (XRDS) of the crystalline derivatives obtained from the addition of a Grignard reagent (Scheme 3B, 13 PhCl and 14 PhCl ). This analysis confirmed the monomeric cis-(2 + 2) identity of 13 and identified the unknown byproduct as a dimeric species with a trans/trans tricyclic core (14).
When the activation of 10 was repeated using different pyridine bases (Scheme 3A), several interesting trends emerged. While electron-rich pyridines did not lead to significant conversion of 10, highly electron-deficient pyridines led to the formation of γ-butyrolactone 15 via deallylation�as is the case in absence of a base. 50 At the 20°C temperature utilized for these studies, sterically crowded collidine produced the base-stabilized adduct 16. 42 When bases of intermediate basicity and steric hindrance were employed, both (2 + 2) adducts 13 and lactone 12 were formed along with dimerized product 14. The halopyridines�particularly 2-fluoropyri-dine�appear appropriately tuned to the desired (2 + 2) behavior with regard to basicity and steric encumbrance.
While the observed dimer species 14 exhibited only trans cyclobutanone ring junctions, no trace of a monomeric trans-(2 + 2) adduct was detected. Significant differences manifest on a monomeric basis between the direct cis-(2 + 2) (Figure 2, TS-6) and trans-(2 + 2) (Figure 2, TS-7), whereby the trans-(2 + 2) is found to be higher in energy than its diastereomer by a barrier surpassing 20 kcal/mol. This can be rationalized by analogy to cis-and trans-cycloheptene, the geometries of which comprise the cores of these transition structures. These consequently exhibit a similar difference in energy, as can be identified by the positions of the exo-and endo-cyclic olefin protons (Figure 2, highlight). 51 Additionally, the resulting trans adduct is 12.7 kcal/mol less stable than the cis, in line with the very few examples of related trans-fused small ring-containing bicycles previously reported in the literature. 29,52−54 We hypothesized that the dimer system is capable of trans/ trans ring fusion as the initial intermolecular interaction does not necessitate ring strain analogous to the monomeric TS-7. This is not the whole picture, however, as we observed that different pyridine bases produce temperature-dependent product distributions (Scheme 4A).
Rationalizing Base Effects. Indeed, employing 2fluoropyridine favored 14, while collidine at elevated temperatures favored the formation of 13 (Scheme 4A). Interestingly, the same 13:14 ratio was observed when the reaction was performed using 2-fluoropyridine at 20°C instead of 120°C, with the dimer product being more favored at even lower temperatures (Scheme 4A). These features indicate that the pyridine base is directly involved in one or more determining steps of the mechanism.
However, the methyl olefin transition structures TS-6 and TS-7 do not require explicit involvement of base and there should be no such kinetic dependence. We, therefore, sought to elucidate potential routes by which an equivalent of a base could intercept these structures. One such possibility arose from our study of the intrinsic reaction coordinate (IRC) of TS-6. This IRC illustrates that the two new bonds of the product iminium cyclobutane 18 are formed in an energetically concerted, bonding-stepwise fashion (Figure 3; see Supporting Information, section 5.7). These bond-forming events are connected by a flat region in the IRC�a feature we have referred to in other contexts as an entropic intermediate 55 � that represents the intervening carbenium ion. We identified stationary points nearby the IRC for a distorted analogue of this monomeric entropic intermediate (17, Figure 3A) and the  Figure 3D) that may be conformationally sampled over the course of the reaction. If such an entropic intermediate were sufficiently kinetically stable, we hypothesized that an equivalent of pyridine base may nucleophilically intercept the cationic species. The resulting complex would adopt the required geometry to produce the observed trans-cyclobutane ring junctions. While DFT geometry optimizations of the requisite dimeric TSs and intermediates did not converge, a representative analysis was successfully conducted for the monomeric system ( Figure  3B   Cyclopropyloxepane 19 presents a conformation analogous to the direct trans-(2 + 2) structure TS-7, with the pyridinium ring adopting a pseudoequatorial orientation. Simultaneous cyclopropyl ring expansion and expulsion of the pyridine base proceed to the trans-cyclobutylidene iminium adduct 20 ( Figure 3C).
While the free energy of the expansion TS (TS-9) is marginally higher than that of the cis-(2 + 2) TS, the small difference in energy suggests that both pathways should be competitive. That the monomeric trans-(2 + 2) analogue of 13 is not observed suggests that the homoallylic carbenium ion 17 is not sufficiently kinetically stable as hypothesized and is not intercepted by the base at a competitive rate. As the trans motif is observed in the dimer species, we propose the dimeric analogue of 17 (21) is sufficiently long-lived to interact with the pyridine base and undergo this interception/ring expansion transformation to the observed trans/trans dimer 14 (Scheme 5).
DFT studies conducted with collidine as the base similarly located TS-10, a trapping transition structure analogous to TS-9 ( Figure 4). This TS exhibits considerable steric crowding and is 5.0 kcal/mol higher in energy than the corresponding cis-(2 + 2) TS. A similar energy barrier for the dimer system would suggest the trans-(2 + 2) dimer should be disfavored. Indeed, this is consistent with our collidine experiments, as the monomeric cis-(2 + 2) cycloadduct is favored 3.3:1. 56 As the formation of 21 should be independent of base, the observed product distribution suggests this initial dimerization is reversible (Scheme 5). An additional consequence of this interception/expansion and reversibility hypothesis is the computational prediction that the monomer/dimer ratio should be dependent on the stoichiometry of the base; a lower concentration of base should yield a higher proportion of cis-(2 + 2) adduct 13 over dimer 14 and vice versa. Indeed, experimentally repeating the 2-fluoropyridine-mediated process with different proportions of base confirms this prediction (Scheme 4B).
These base concentration studies also found that substoichiometric base loadings resulted in the appearance of the deallylated γ-lactone side product 15, a side product that is also observed with the use of highly electron-deficient�and therefore less basic 57 �pyridines (Scheme 3A).
This had been previously observed by the Maulide group, whereby omitting the base entirely demonstrated utility for the synthesis of γ-lactones from amides. 50 We sought a mechanistic understanding of this side reactivity (Scheme 6) and identified a competing pathway proceeding through the doubly cationic�though surprisingly low-energy�cyclic species 28. This structure, which readily deallylates to produce an unsubstituted γ-lactone (15, ΔΔG ⧧ = +1.2 kcal/mol) after hydrolysis, is accessed by a cyclization TS-11 that is expected to be highly competitive with the base-mediated isomerization TS-14, key to the above Claisen/(2 + 2) processes (ΔΔG ⧧ = +1.3 kcal/mol). Kinetically, we would expect this deallylation  Journal of the American Chemical Society pubs.acs.org/JACS Article process to predominate when the relative concentration of the base is low, which corroborates our experimental findings (see Scheme 4). Steering toward (2 + 2) Products: the Reactant Olefin as a Handle. Having successfully altered the chemoselectivity of this keteniminium ion cascade, we hypothesized that additional increases in the olefin electron density may further favor the formation of the (2 + 2) adduct. We sought to test this using substituted aryl olefin derivatives (30a−f, Figure  5A). DFT calculations conducted on derivatives 30a and 30c suggest the barrier to the cis-(2 + 2) TS is even lower than for methyl derivative 10 (ΔΔG ⧧ = −0.9 kcal/mol vs Claisen chair). To our delight, the aryl olefin substrates delivered high yields of the (2 + 2) adduct�in particular, the 4methoxyphenyl derivative 30a, which produced a 65% NMR yield of the monomeric cis adduct 31a�and were in close agreement with the computationally predicted product ratio (see Supporting Information, section 5.8). The structure of the cis adduct of these aryl derivatives could be unequivocally assessed by XRDS of 31f, for which enantiomerically pure monocrystals were obtained 58 ( Figure 5C). Additionally, we indeed observed a correlation between olefin electron density and (2 + 2) adduct yield, corroborating our hypothesis that electron-rich olefins promote (2 + 2) activity and simultaneously suppress allyl-lactone production ( Figure 5A).
We sought to minimize dimer formation and performed concentration studies using 30d ( Figure 5B). As anticipated, the production of monomeric cis-(2 + 2) adduct 31d was maximized at lower concentrations, while dimer 33d could be favored at higher concentrations. Production of lactone 32d was also inhibited at higher concentrations, consistent with an increasingly competitive trapping of the keteniminium ion by the allyl moiety of another activated substrate such as the aryl olefin congeners of 11 or 29.
In contrast to the methyl olefin derivative 10, the aryl olefin 30d formed the dimer compound 33d, exhibiting both trans/  Figure 5B). These diastereomers were obtained as a 1.5:1 mixture in favor of the trans/trans derivative and could be isolated pure by preparative high-performance liquid chromatography and fully characterized by NMR spectroscopy as well as XRDS ( Figure 5C). Analysis of the IRC of the monomeric cis-(2 + 2)-forming TS for analogues of 30 indicates this species proceeds to a stable carbocation, analogous to the entropic intermediate of the methyl olefin substrate 17 and methyl olefin dimer 21 (see Supporting Information, section 5.9). It is reasonable to assume that the benzylic stabilization of this carbocation is the reason for the formation of the two observed diastereomers, as the stability imparted permits the molecule to sample conformers capable of proceeding to both the trans/trans and trans/cis configurations. After reprogramming this process toward (2 + 2) adduct formation, we attempted to formulate an enantioselective variant by installing stereogenic elements on the keteniminium ion. Pleasingly, reactions conducted with α-methoxymethylpyrrolidine substrate 34 demonstrated asymmetric induction with a small but detectable enantiomeric ratio (e.r.) of 58:42 (Scheme 7), a selectivity in-line with previous keteniminium ion processes. 24,25,59 Our DFT analysis of the four diastereomeric TSs finds that, while one pair of diastereomers� producing a single enantiomer on hydrolysis of the resulting iminium ion�is indeed favored, there is considerable conformational flexibility to the scaffold that renders the energy gap minute (predicted: 71:29 e.r. at 0°C; see Supporting Information, section 5.10). While minor, this result does provide an interesting proof-of-concept for further experimental and computational development. Other chiral amine scaffolds, such as MacMillan's imidazolidinones, 60−63 were found to exhibit larger energy gaps between diastereomeric transition structures as determined by DFT (see Supporting Information, section 5.11). Unfortunately, substrate 35 did not produce observable (2 + 2) or Claisen products, presumably either due to side reactivity between the keteniminium ion and imidazolidinone pendent aryl ring or competition for Tf 2 O between both amide groups. 64

■ CONCLUSIONS
We have conducted a thorough computational analysis of Maulide's 2010 Bellus−Claisen-type rearrangement of keteniminium ion scaffolds, identifying a significant opportunity to alter the observed chemoselectivity of the reaction toward an intramolecular (2 + 2) reaction. Computational predictions of substrates with greater electron density on the olefin moiety indicated that critical cyclization TSs should become highly competitive with the Claisen-type TSs, a prediction that was experimentally confirmed. A remarkable unexpected product forming in these reactions was identified as a dimeric species resulting from twofold (2 + 2) cycloadditions. We provide potential mechanisms�with experimental backing�for the production of monomeric cis-(2 + 2) adduct and (2 + 2) dimers, as well as DFT rationalization of a competing deallylation side reaction. We demonstrated experimentally the response of the (2 + 2) cyclization to olefin electronics as well as a proof-of-concept enantioselective (2 + 2) variant. These data demonstrate the mutability of useful intramolecular processes, illustrate the impact of small changes to scaffolds, and highlight the beneficial synergy of computation and experimentation in modern synthetic organic chemistry. Our study elucidates subtle differences between reaction pathways and demonstrates the control over chemoselectivity necessary for future applications of keteniminium ion chemistry to total synthesis and the further advancement of this versatile functional group. ■ ASSOCIATED CONTENT
Computational and experimental methods and procedures, energies, Cartesian coordinates of optimized structures, and experimental characterization data and spectra (PDF) XYZ files for optimized structures (ZIP) diastereomeric ratio DTBMP 2,6-(di-tert-butyl)-4-methylpyridine IRC intrinsic reaction coordinate IS internal standard e.r. enantiomeric ratio XRDS X-ray diffraction spectroscopy